-26 Host response to viral pathogens relies heavily on T cells

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  • With intracellular parasites, viruses and some microorganisms, cytotoxic T cells are particularly important. After activation, cytotoxic T cells attacked infected host cells killing them.

The response to a viral infection is quite different from that seen in a bacterial infection. Viral infections are intracellular for the most part, while the case we described above was extracellular. This has two implications. First, much of the damage is going to occur inside infected cells. Second, elimination of the infection is going to require destruction of host cells. Therefore, the immune system needs a method of discriminating virally infected cells from healthy cells. Fortunately our bodies have just such a mechanism and it involves the MHC I molecules. In general, cell-mediated immunity is much more important for clearing a viral infection. Figure 15-27 summarizes the hosts response to infection with influenza virus.

Immune response to influenza infection

Figure 15.27. Immune response to influenza infection. An immune defense against a viral infection is more dependent on T cells and less dependent on antibodies. Cytotoxic T cells are important in killing virally infected cells. In step (1) influenza virus enters the cell and begins to replicate (2). Viral proteins fill the cytoplasm (3). Most go on to form influenza virus and escape (4). The presence of viral proteins in the cytoplasm also causes the production of α-interferon (5). Some viral proteins are degraded and end up being displayed in MHC I molecules (6). Passing Tc cells will test the MHC I molecule presenting foreign antigen and a fraction will be activated by it. Activated Tc cells are directed to differentiate into cytotoxic T cells by TH1 cells. Activated cytotoxic T cells then attack other virally infected cells displaying viral antigens in the MHC I molecules that the T cells react to. Viral antigens are also presented to B cells producing antibodies in a similar fashion to that described in Section 15-25. These antibodies attack free virus, agglutinating it and making it available for phagocytosis (9).

Influenza virus is a good example to study because it illustrates many of the salient points of viral infection and is also an important human pathogen. However, remember that the specific response of the immune system is dependent upon the particular pathogen. Many of the mechanisms that we describe here come into play in other viral infections, but the exact response is always unique to the particular viral agent.

Influenza is a very contagious disease that easily spreads through respiratory droplets expelled by infected individuals. For this example, imagine that an influenza sufferer has just sneezed on their hand and then opened a door, contaminating the door handle. Another person touching the handle can picked up droplets containing 100,000,000 flu viruses and a subsequent touch can transfer 1,000,000 to the nasal or oral cavity. Some of them then land at the back of the throat. Again, the low pH and unfriendly environment created by the normal flora and host proteins cause the vast majority of the viruses to be inactivated. Those that do survive bind to sialic acid-containing proteins or lipids on the surface of throat epithelial cells and enter by receptor-mediated endocytosis. A drop in the pH of the endosome causes a conformational change in the virus and the release of the eight genomic fragments of influenza virus into the cell. Up until this point, the immune system has no indication that anything is amiss.

Virus begins to replicate and viral proteins accumulate in the infected cell. Some of these proteins are degraded by host cell machinery and the peptide fragments are transported into the endoplasmic reticulum, where they combine with newly synthesized MHC I molecules. The MHC I molecules loaded with foreign viral antigens now find their way to the surface of the cell. The infected cell also begins to produce and secrete α-interferon. This notifies surrounding cells of viral infection and induces them to produce compounds that interfere with viral replication making further infection more difficult.

Virally infected cells begin to release flu virus particles into the surrounding tissues. The presence of viral particles and the death of virally infected cells begin the process of inflammation as described for S. pyogenes infection. This causes the characteristic redness, soreness and swelling in the back of the throat and the induction of fever observed in influenza. At this point, macrophages and dendritic cells take up viruses and viral debris, process them and add to MHC II molecules for presentation to T helper cells. TH1 cells detect the presented antigen and those that match are activated and begin to secrete IL-2, which has several effects on other T and B cells responding to the infection.

Mucous secretion from the intensifying inflammation begins to cause a runny nose and coughing. The release of interferon and IL1 contribute to the aches and fever associated with influenza. As the concentration of virus increases in the body, these symptoms intensify.

Cytotoxic T cells (Tc cells) roaming in the tissues encounter infected cells presenting viral antigens in their MHC I molecules. Those that have TCRs that respond to the antigen are activated to begin clonal expansion and develop into active cytotoxic cells under the influence of the TH1 cells. During the next encounter with a virally infected cell, these cells again recognize the viral antigen being presented in an MHC I molecule using their TCR, but this time, they are activated to attack the cell. The Tc cell binds to the infected cell and begins a destructive cycle. A number of cytokines, including γ-interferon and tumor necrosis factor (TNF), are secreted by the Tc cell. These factors limit viral replication in the target cell and also attract phagocytes to the area. The Tc cells also produce molecules that elicit a form of programmed cell death (apoptosis) in the target cell, essentially telling the cell to kill itself. Phagocytes that enter the area then clean up any remaining viral debris. As in the case of B cells, some of the Tc cells of the clonal expansion do not differentiate, but remain as memory cells in preparation for the next viral challenge by this viral strain.

Phagocytized virus is also presented to TH2 cells that respond by activating in a manner identical to that described earlier for bacterial infections. Virally infected cells also stimulate B cells that respond by clonal expansion and differentiation into plasma cells, resulting in the formation of antibodies against viral antigens. Antibodies are commonly raised against hemagglutinin and neuraminidase, two proteins on the outer surface of the virus. In most viral infections, antibody is not as important as in bacterial infections, but it does have several consequences. Antibodies bound to virus cause them to agglutinate, precipitate them out of solution and slow their spread through the body. Many effective antibodies block the receptor site of the virus and prevent its attachment to new host cells. These types of antibodies are especially useful in stopping subsequent infections by the same virus. Antibodies attached to virus also assist phagocytes in the efficient uptake of viral particles.

Free virus in the body is eliminated by the action of antibodies and phagocytes and the activated Tc cells destroy any virally infected cells. As the load of virus present in the body decreases, T suppressor cells help the immune response abate. After infection, subsequent attack by this strain of influenza virus is prevented by the action of T and B memory cells.

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